Many severe diseases are linked to malfunctions of the TGFβ-induced signaling pathway. An increased tissue level of TGFβ is believed to be a factor in the development of idiopathic pulmonary fibrosis and myocardial fibrosis, for example. Furthermore, high local tissue levels of TGFβ can allow the maintenance and progression of some types of cancer cells. The down-regulation of TGFβ signaling therefore can reduce the viability of such tumor cells.
TGFβ isoforms are ˜25 kDa homodimeric molecules with a similar structural framework in which two monomers are covalently linked via a disulfide bridge. The mammalian isoforms share a sequence identity of 70-82%, but have non-overlapping activities in vascular development and the regulation of immune cell function. Three TGFβ isoforms are present in humans: TGFβ1, TGFβ2, and TGFβ3 (Swiss Prot accession numbers P01137, P08112, and P10600, respectively). TGFβ1 and TGFβ3 trigger a cellular signaling cascade upon binding to the extracellular domains of two transmembrane receptors, known as TGFβ receptor types I and II. TGFβ2 binding is also thought to involve TGFβ receptor types I and II, as well as TGFβ receptor type III.
Antibody molecules the can bind human TGFβ1, TGFβ2, and TGFβ3 have been generated (e.g., U.S. Pat. No. 7,723,486 to Genzyme). Grütter et al. (2008) Proc. Nat'l Acad. Sci. USA 105(51): 20251-56, for example, disclose GC1008, a human IgG4 monoclonal antibody (MAb) in clinical development for treating malignancy and fibrotic diseases. GC1008 is a “pan-specific” TGFβ neutralizing antibody, because it can neutralize all three human TGFβ isoforms. GC1008 binds to human TGFβ1, TGFβ2, and TGFβ3 with similar affinities. The TGFβ epitope recognized by GC1008 overlaps the TGFβ binding site for TGFβ receptor types I and II, which is believed to underlie the neutralizing ability of GC1008. Grütter et al. disclose the three dimensional structure of a GC1008 Fab fragment in complex with TGFβ3 at a resolution of 3.1 Å. The complex consists of a TGFβ3 homodimer flanked by two GC1008 Fab fragments. See also Proteopedia entry 3eo0, “Structure of the Transforming Growth Factor-Beta Neutralizing Antibody GC-1008,” on the Internet at proteopedia.org/wiki/index.php/3eo0 (last modified Oct. 20, 2012); and Proteopedia entry 3eo1, “Structure of the Fab Fragment of GC-1008 in Complex with Transforming Growth Factor-Beta 3,” on the Internet at proteopedia.org/wiki/index.php/3eo1 (last modified Oct. 20, 2012).